CN108033899A - The preparation method of one kind (R) -6- cyano group -5- hydroxyl -3- carbonyl hecanoic acid t-butyl esters - Google Patents
The preparation method of one kind (R) -6- cyano group -5- hydroxyl -3- carbonyl hecanoic acid t-butyl esters Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title claims description 8
- 239000002253 acid Substances 0.000 title description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 18
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims abstract description 15
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- LOQFROBMBSKWQY-ZCFIWIBFSA-N ethyl (3r)-4-cyano-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CC#N LOQFROBMBSKWQY-ZCFIWIBFSA-N 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000008346 aqueous phase Substances 0.000 claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- ZUYPZFBFGJUZNA-JTQLQIEISA-N C(#N)C[C@@H](CC(CC(=O)OC(C)(C)C)=C=O)O Chemical compound C(#N)C[C@@H](CC(CC(=O)OC(C)(C)C)=C=O)O ZUYPZFBFGJUZNA-JTQLQIEISA-N 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 6
- 230000003068 static effect Effects 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims 2
- YKAWMIUWRFYNIS-UHFFFAOYSA-N ethyl 2-cyano-3-hydroxybutanoate Chemical compound CCOC(=O)C(C#N)C(C)O YKAWMIUWRFYNIS-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 229910052744 lithium Inorganic materials 0.000 abstract description 3
- 229910052708 sodium Inorganic materials 0.000 abstract description 3
- 239000011734 sodium Substances 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 2
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- CCQZKUWBWPJBPY-MRVPVSSYSA-N tert-butyl (5r)-6-cyano-5-hydroxy-3-oxohexanoate Chemical compound CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N CCQZKUWBWPJBPY-MRVPVSSYSA-N 0.000 description 3
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 description 2
- 229960001770 atorvastatin calcium Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- -1 1,1-dimethylethyl ester Chemical class 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- WLRFCPQXWBDLRG-QMMMGPOBSA-N CC(C)(C)OC(CC(C[C@@H](CCl)O)=O)=O Chemical compound CC(C)(C)OC(CC(C[C@@H](CCl)O)=O)=O WLRFCPQXWBDLRG-QMMMGPOBSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- LHBPNZDUNCZWFL-BYPYZUCNSA-N N#CC[C@@H](CCl)O Chemical compound N#CC[C@@H](CCl)O LHBPNZDUNCZWFL-BYPYZUCNSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 108010013164 halohydrin dehalogenase Proteins 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- NRUBUZBAZRTHHX-UHFFFAOYSA-N lithium;propan-2-ylazanide Chemical compound [Li+].CC(C)[NH-] NRUBUZBAZRTHHX-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- DANUJARGWMPVQX-UHFFFAOYSA-N tert-butyl hexanoate Chemical compound CCCCCC(=O)OC(C)(C)C DANUJARGWMPVQX-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种(R)‑6‑氰基‑5‑羟基‑3‑羰基己酸叔丁酯的制备方法。在氮气保护下，将乙酸叔丁酯和1,8‑二氮杂二环十一碳‑7‑烯加入到2‑甲基四氢呋喃中制备得到A溶液。将(R)‑4‑氰基‑3‑羟基丁酸乙酯溶解于2‑甲基四氢呋喃中，得到B溶液；将A溶液、B溶液同时滴加到少量2‑甲基四氢呋喃中，控制反应温度20‑30℃、A溶液、B溶液同时滴完，滴完后搅拌反应1‑5小时。在反应体系中滴加水，静止分层。有机相减压浓缩得到R)‑6‑氰基‑5‑羟基‑3‑羰基己酸叔丁酯，同时回收溶剂，水相浓缩回收1,8‑二氮杂二环十一碳‑7‑烯。本发明不需要低温液氮，能耗低，不使用金属锂、钠等危险试剂，工艺安全，反应后溶剂、试剂都能回收，绿色环保。The invention discloses a preparation method of (R)-6-cyano-5-hydroxy-3-carbonylhexanoic acid tert-butyl ester. Under nitrogen protection, tert-butyl acetate and 1,8-diazabicycloundec-7-ene were added to 2-methyltetrahydrofuran to prepare A solution. Dissolve ethyl (R)-4-cyano-3-hydroxybutyrate in 2-methyltetrahydrofuran to obtain solution B; add solution A and solution B to a small amount of 2-methyltetrahydrofuran simultaneously to control the reaction The temperature is 20-30°C, the A solution and the B solution are dropped at the same time, and the reaction is stirred for 1-5 hours after the drop is completed. Water was added dropwise to the reaction system, and the layers were separated. The organic phase is concentrated under reduced pressure to obtain R)-6-cyano-5-hydroxyl-3-carbonylhexanoic acid tert-butyl ester, while reclaiming the solvent, the aqueous phase is concentrated and reclaimed 1,8-diazabicycloundeca-7- alkene. The invention does not require low-temperature liquid nitrogen, has low energy consumption, does not use dangerous reagents such as metal lithium and sodium, has safe process, can recover solvents and reagents after reaction, and is environmentally friendly.
Description
技术领域technical field
本发明属阿托伐他汀钙中间体的制备领域，具体涉及一种(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯的制备方法。The invention belongs to the field of preparation of atorvastatin calcium intermediates, in particular to a preparation method of (R)-6-cyano-5-hydroxy-3-carbonylhexanoic acid tert-butyl ester.
背景技术Background technique
(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯，英文名：Hexanoic acid,6-cyano-5-hydroxy-3-oxo-,1,1-dimethylethyl ester,(5R)-，CAS No.：125988-01-4,结构式如下：(R)-tert-butyl 6-cyano-5-hydroxy-3-carbonylhexanoate, English name: Hexanoic acid,6-cyano-5-hydroxy-3-oxo-,1,1-dimethylethyl ester,(5R )-, CAS No.: 125988-01-4, the structural formula is as follows:
(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯是合成HMG-CoA还原抑制剂阿托伐他汀钙的关键中间体。现有的合成技术主要有：(R)-tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate is a key intermediate in the synthesis of HMG-CoA reduction inhibitor atorvastatin calcium. The existing synthesis techniques mainly include:
CN105567655公开了重组的卤醇脱卤酶催化合成。CN105567655 discloses the catalytic synthesis of recombinant halohydrin dehalogenase.
此合成方法原料不容易得到。The raw materials of this synthetic method are not easy to obtain.
CN103420871公开了通过溴乙酸叔丁酯制备成锌试剂进一步反应得到(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯。CN103420871 discloses that tert-butyl bromoacetate is prepared into zinc reagent and further reacted to obtain (R)-6-cyano-5-hydroxyl-3-carbonylhexanoic acid tert-butyl.
CN102766072公开了乙酸叔丁酯与钠氢或钠反应，进一步与(R)-4-氰基-3-羟基丁酸乙酯反应制备(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯。CN102766072 discloses that tert-butyl acetate reacts with sodium hydrogen or sodium, and further reacts with (R)-4-cyano-3-hydroxybutyric acid ethyl ester to prepare (R)-6-cyano-5-hydroxyl-3-carbonyl tert-butyl caproate.
IN2009CH00540公开了乙酸叔丁酯与(R)-4-氰基-3-羟基丁酸乙酯在六甲基硅胺锂作用下制备(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯的方法，反应在-70-80℃下进行。IN2009CH00540 discloses the preparation of (R)-6-cyano-5-hydroxyl-3-carbonyl by tert-butyl acetate and ethyl (R)-4-cyano-3-hydroxybutyrate under the action of lithium hexamethylsilylamide For the method of tert-butyl hexanoate, the reaction is carried out at -70-80°C.
WO2008042876、EP1659110、US20090216029，Stach,Jan(Collection ofCzechoslovak Chemical Communications,73(2),229-246；2008)用异丙基胺锂作为强碱，作用于乙酸叔丁酯，再与(R)-4-氰基-3-羟基丁酸乙酯反应。WO2008042876, EP1659110, US20090216029, Stach, Jan (Collection of Czechoslovak Chemical Communications, 73 (2), 229-246; 2008) use lithium isopropylamide as a strong base to act on tert-butyl acetate, and then react with (R)-4 - Ethyl cyano-3-hydroxybutyrate reaction.
反应首先在-40℃形成乙酸叔丁酯的烯醇结构，再在-78℃发生Claisen缩合反应制备(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯。WO2011048425为解决上述反应低温控制的难点，采用了连续化的制备工艺，将反应时间控制在2.4秒。上述方法的低温需要采用液氮来冷却，液氮在使用过程中难以回收，导致能耗很高；无论是金属锂还是金属钠、钠氢，遇水即燃，工艺非常危险；以上工艺都存在产生大量盐的废弃物，后续处理困难，环境污染大。The reaction first forms the enol structure of tert-butyl acetate at -40°C, and then produces (R)-6-cyano-5-hydroxy-3-oxoylhexanoic acid tert-butyl through a Claisen condensation reaction at -78°C. In WO2011048425, in order to solve the above-mentioned difficulties in low temperature control of the reaction, a continuous preparation process was adopted to control the reaction time at 2.4 seconds. The low temperature of the above method needs to be cooled by liquid nitrogen, which is difficult to recycle during use, resulting in high energy consumption; whether it is metallic lithium, metallic sodium, or sodium hydrogen, it will ignite when it meets water, and the process is very dangerous; all of the above processes exist The waste that produces a large amount of salt is difficult to follow up and causes serious environmental pollution.
发明内容Contents of the invention
针对现有技术存在的问题，本发明公开了一种(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯的制备方法，该方法能耗低、操作安全、环境友好。Aiming at the problems existing in the prior art, the invention discloses a preparation method of (R)-6-cyano-5-hydroxy-3-oxoylhexanoic acid tert-butyl ester, which has low energy consumption, safe operation and environmental friendliness .
在氮气保护下，将乙酸叔丁酯和1,8-二氮杂二环十一碳-7-烯加入到2-甲基四氢呋喃中，升温到回流状态，搅拌反应1-5小时，缓慢降温到25-30℃，制备得到A溶液。乙酸叔丁酯与1,8-二氮杂二环十一碳-7-烯的摩尔比为1:1-1.05；2)将(R)-4-氰基-3-羟基丁酸乙酯溶解于2-甲基四氢呋喃中，得到B溶液；3)将A溶液、B溶液同时滴加到少量2-甲基四氢呋喃中，控制反应温度20-30℃、A溶液、B溶液同时滴完，滴完后搅拌反应1-5小时；4)在反应体系中滴加水，水的体积百分数为2-甲基四氢呋喃的5-10％，静止分层；5)有机相减压浓缩得到R)-6-氰基-5-羟基-3-羰基己酸叔丁酯，同时回收溶剂，水相浓缩回收1,8-二氮杂二环十一碳-7-烯。Under the protection of nitrogen, add tert-butyl acetate and 1,8-diazabicycloundec-7-ene into 2-methyltetrahydrofuran, raise the temperature to reflux state, stir for 1-5 hours, and slowly cool down At 25-30°C, A solution was prepared. The molar ratio of tert-butyl acetate to 1,8-diazabicycloundec-7-ene is 1:1-1.05; 2) Ethyl (R)-4-cyano-3-hydroxybutyrate Dissolve in 2-methyltetrahydrofuran to obtain solution B; 3) Add solution A and solution B dropwise to a small amount of 2-methyltetrahydrofuran at the same time, control the reaction temperature at 20-30°C, and drop solution A and solution B at the same time, After dripping, stirring and reacting for 1-5 hours; 4) adding water dropwise to the reaction system, the volume percentage of water is 5-10% of 2-methyltetrahydrofuran, and static layering; 5) concentrating the organic phase under reduced pressure to obtain R)- tert-butyl 6-cyano-5-hydroxy-3-carbonylhexanoate, while recovering the solvent, and concentrating the aqueous phase to recover 1,8-diazabicycloundec-7-ene.
具体实施方式Detailed ways
一种(R)-6-氰基-5-羟基-3-羰基己酸叔丁酯的制备方法如下：A preparation method of (R)-6-cyano-5-hydroxyl-3-carbonylhexanoic acid tert-butyl ester is as follows:
在氮气保护下，将乙酸叔丁酯和1,8-二氮杂二环十一碳-7-烯加入到2-甲基四氢呋喃中，升温到回流状态，搅拌反应1-5小时，缓慢降温到25-30℃，制备得到A溶液。乙酸叔丁酯与1,8-二氮杂二环十一碳-7-烯的摩尔比为1:1-1.05；2)将(R)-4-氰基-3-羟基丁酸乙酯溶解于2-甲基四氢呋喃中，得到B溶液；3)将A溶液、B溶液同时滴加到少量2-甲基四氢呋喃中，控制反应温度20-30℃、A溶液、B溶液同时滴完，滴完后搅拌反应1-5小时；4)在反应体系中滴加水，水的体积百分数为2-甲基四氢呋喃的5-10％，静止分层；5)有机相减压浓缩得到R)-6-氰基-5-羟基-3-羰基己酸叔丁酯，同时回收溶剂，水相浓缩回收1,8-二氮杂二环十一碳-7-烯。Under the protection of nitrogen, add tert-butyl acetate and 1,8-diazabicycloundec-7-ene into 2-methyltetrahydrofuran, raise the temperature to reflux state, stir for 1-5 hours, and slowly cool down At 25-30°C, A solution was prepared. The molar ratio of tert-butyl acetate to 1,8-diazabicycloundec-7-ene is 1:1-1.05; 2) Ethyl (R)-4-cyano-3-hydroxybutyrate Dissolve in 2-methyltetrahydrofuran to obtain solution B; 3) Add solution A and solution B dropwise to a small amount of 2-methyltetrahydrofuran at the same time, control the reaction temperature at 20-30°C, and drop solution A and solution B at the same time, After dripping, stirring and reacting for 1-5 hours; 4) adding water dropwise to the reaction system, the volume percentage of water is 5-10% of 2-methyltetrahydrofuran, and static layering; 5) concentrating the organic phase under reduced pressure to obtain R)- tert-butyl 6-cyano-5-hydroxy-3-carbonylhexanoate, while recovering the solvent, and concentrating the aqueous phase to recover 1,8-diazabicycloundec-7-ene.
实施例1：Example 1:
在氮气保护下将116克乙酸叔丁酯和160克1,8-二氮杂二环十一碳-7-烯加入到500mL 2-甲基四氢呋喃中,升温到回流状态，搅拌反应5小时，缓慢降温到30℃，制备得到A溶液，将150克(R)-4-氰基-3-羟基丁酸乙酯溶解于100mL 2-甲基四氢呋喃中，制备得到B溶液，将A溶液和B溶液通过两个恒流泵滴加到100mL 2-甲基四氢呋喃中，强烈搅拌，控制A溶液的滴加速度是B溶液的5倍左右，通过滴加速率控制反应温度在20℃，同时滴完，滴完后搅拌反应1小时，滴加水35mL，静止分层。有机相浓缩得到R)-6-氰基-5-羟基-3-羰基己酸叔丁酯220克，液相色谱检测其光学纯度为99.5％(Chiracel OD column)。1H-NMR(CDCl3,ppm)δ4.40-4.42(m,1H,CHO),3.58(s,1H,OH),3.40(s,2H,COCH2CO),2.86-2.88(d,2H,NCCH2),2.60-2.62(m,2H,CHCH2CO),1.49(s,9H,C(CH3)3)。同时回收溶剂680ml，水相浓缩回收1,8-二氮杂二环十一碳-7-烯135克。Under the protection of nitrogen, 116 grams of tert-butyl acetate and 160 grams of 1,8-diazabicycloundec-7-ene were added to 500 mL of 2-methyltetrahydrofuran, the temperature was raised to reflux, and the reaction was stirred for 5 hours. Slowly lower the temperature to 30°C to prepare solution A. Dissolve 150 g of (R)-4-cyano-3-hydroxybutyrate ethyl ester in 100 mL of 2-methyltetrahydrofuran to prepare solution B. Mix solution A and B Add the solution dropwise into 100mL 2-methyltetrahydrofuran through two constant flow pumps, stir vigorously, control the drop rate of solution A to be about 5 times that of solution B, and control the reaction temperature at 20°C through the drop rate, and drop it at the same time. After the dropwise reaction was stirred for 1 hour, 35 mL of water was added dropwise, and the mixture was separated into layers. The organic phase was concentrated to obtain 220 g of tert-butyl R)-6-cyano-5-hydroxy-3-carbonylhexanoate, the optical purity of which was detected by liquid chromatography was 99.5% (Chiracel OD column). 1 H-NMR(CDCl 3 ,ppm)δ4.40-4.42(m,1H,CHO),3.58(s,1H,OH),3.40(s,2H,COCH 2 CO),2.86-2.88(d,2H , NCCH 2 ), 2.60-2.62 (m, 2H, CHCH 2 CO), 1.49 (s, 9H, C(CH 3 ) 3 ). At the same time, 680 ml of solvent was recovered, and 135 grams of 1,8-diazabicycloundec-7-ene was recovered by concentration of the aqueous phase.
实施例2：Example 2:
在氮气保护下将116克乙酸叔丁酯和152克1,8-二氮杂二环十一碳-7-烯加入到500mL 2-甲基四氢呋喃中,升温到回流状态，搅拌反应1小时，缓慢降温到25℃，制备得到A溶液，将157克(R)-4-氰基-3-羟基丁酸乙酯溶解于100mL 2-甲基四氢呋喃中，制备得到B溶液，将A溶液和B溶液通过两个恒流泵滴加到100mL 2-甲基四氢呋喃中，强烈搅拌，控制A溶液的滴加速度是B溶液的5倍左右，通过滴加速率控制反应温度在30℃，同时滴完，滴完后搅拌反应5小时，滴加水70mL，静止分层。有机相浓缩得到R)-6-氰基-5-羟基-3-羰基己酸叔丁酯214克，同时回收溶剂680ml，水相浓缩回收1,8-二氮杂二环十一碳-7-烯138克。Under the protection of nitrogen, 116 grams of tert-butyl acetate and 152 grams of 1,8-diazabicycloundec-7-ene were added to 500 mL of 2-methyltetrahydrofuran, the temperature was raised to reflux, and the reaction was stirred for 1 hour. Slowly lower the temperature to 25°C to prepare solution A. Dissolve 157 g of (R)-4-cyano-3-hydroxybutyrate ethyl ester in 100 mL of 2-methyltetrahydrofuran to prepare solution B. Mix solution A and B Add the solution dropwise to 100mL 2-methyltetrahydrofuran through two constant flow pumps, stir vigorously, control the drop rate of solution A to be about 5 times that of solution B, control the reaction temperature at 30°C through the drop rate, and finish the drop at the same time. After the dropwise reaction was stirred for 5 hours, 70 mL of water was added dropwise, and the mixture was separated into layers. The organic phase was concentrated to obtain 214 grams of tert-butyl R)-6-cyano-5-hydroxy-3-carbonylhexanoate, and 680 ml of solvent was recovered at the same time, and the aqueous phase was concentrated to recover 1,8-diazabicycloundecan-7 -ene 138 grams.
实施例3：Example 3:
在氮气保护下将116克乙酸叔丁酯和152克回收的1,8-二氮杂二环十一碳-7-烯加入到500mL回收的2-甲基四氢呋喃中,升温到回流状态，搅拌反应1小时，缓慢降温到25℃，制备得到A溶液，将157克(R)-4-氰基-3-羟基丁酸乙酯溶解于100mL回收的2-甲基四氢呋喃中，制备得到B溶液，将A溶液和B溶液通过两个恒流泵滴加到100mL回收的2-甲基四氢呋喃中，强烈搅拌，控制A溶液的滴加速度是B溶液的5倍左右，通过滴加速率控制反应温度在30℃，同时滴完，滴完后搅拌反应3小时，滴加水70mL，静止分层。有机相浓缩得到R)-6-氰基-5-羟基-3-羰基己酸叔丁酯195克，同时回收溶剂630ml，水相浓缩回收1,8-二氮杂二环十一碳-7-烯127克。Under nitrogen protection, 116 grams of tert-butyl acetate and 152 grams of reclaimed 1,8-diazabicycloundec-7-ene were added to 500 mL of reclaimed 2-methyltetrahydrofuran, heated to a reflux state, and stirred React for 1 hour, slowly lower the temperature to 25 ° C, prepare A solution, dissolve 157 g of (R)-4-cyano-3-hydroxybutyrate ethyl ester in 100 mL of recovered 2-methyltetrahydrofuran, and prepare B solution , Add solution A and solution B dropwise into 100mL of recovered 2-methyltetrahydrofuran through two constant flow pumps, stir vigorously, control the drop rate of solution A to be about 5 times that of solution B, and control the reaction temperature through the drop rate At 30°C, dropwise was completed at the same time, and after the dropwise reaction was stirred for 3 hours, 70 mL of water was added dropwise, and the layers were statically separated. The organic phase was concentrated to obtain 195 grams of tert-butyl R)-6-cyano-5-hydroxy-3-carbonylhexanoate, and 630 ml of solvent was recovered at the same time, and the aqueous phase was concentrated to recover 1,8-diazabicycloundec-7 -ene 127 grams.
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